The goal of this research proposal is to combine organic synthesis with recent advances in structural biology to make significant contributions both to the fields of molecular recognition and neurobiology. We propose to develop fourfold symmetrical, synthetic ligands that recognize tetrameric ion channels, in particular potassium channels. The primary goal of the proposed research is to provide a large set of molecular probes that discriminate among different types of potassium channels or modulate their functional properties. These compounds could be useful tools in neurobiological studies. It is hoped that these compounds will eventually surpass antibodies and peptide toxins in the selective recognition of potassium channels. Ultimately, the proposed research might lead to novel therapeutic agents against various ailments such as autoimmune disorders, diabetes as well as mental or cardiac diseases. Specifically, the synthesis and biological evaluation of designed ligands for voltage-gated potassium channels such as KvAP, Shaker, and human Kv1.x channels is proposed. Pharmacologically relevant Kv1.x channels such as Kv1.3 or Kv1.5 will receive special attention. The ability of the synthetic ligands to bind to different functional states of a given channel will be evaluated.